Methods and apparatus for intravascularly-induced neuromodulation

ABSTRACT

Methods and apparatus are provided for intravascularly-induced neuromodulation using a pulsed electric field, e.g., to effectuate irreversible electroporation or electrofusion, necrosis and/or inducement of apoptosis, alteration of gene expression, changes in cytokine upregulation, etc., in target neural fibers. In some embodiments, the intravascular PEF system comprises a catheter having a pair of bipolar electrodes for delivering the PEF, with a first electrode positioned on a first side of an impedance-altering element and a second electrode positioned on an opposing side of the impedance-altering element. A length of the electrodes, as well as a separation distance between the first and second electrodes, may be specified such that, with the impedance-altering element deployed in a manner that locally increases impedance within a patient&#39;s vessel, e.g., with the impedance-altering element deployed into contact with the vessel wall at a treatment site within the patient&#39;s vasculature, a magnitude of applied voltage delivered across the bipolar electrodes necessary to achieve desired neuromodulation is reduced relative to an intravascular PEF system having similarly spaced electrodes but no (or an undeployed) impedance-altering element. In a preferred embodiment, the impedance-altering element comprises an inflatable balloon configured to locally increase impedance within a patient&#39;s vasculature. The methods and apparatus of the present invention may be used to modulate a neural fiber that contributes to renal function.

RELATED APPLICATIONS INCORPORATED BY REFERENCE

The present application is a continuation of U.S. patent applicationSer. No. 14/335,016, filed Jul. 7, 2014, now U.S. Pat. No. 9,827,040,which is a continuation of U.S. patent application Ser. No. 13/934,133,filed Jul. 2, 2013, now U.S. Pat. No. 8,818,514, which is a continuationof U.S. patent application Ser. No. 12/827,700, filed Jun. 30, 2010, nowabandoned, which is a divisional of U.S. patent application Ser. No.11/266,993, filed Nov. 4, 2005, now U.S. Pat. No. 7,756,583, which is acontinuation-in-part of U.S. patent application Ser. No. 11/129,765,filed on May 13, 2005, now U.S. Pat. No. 7,653,438, which claims thebenefit of U.S. Provisional Application No. 60/616,254, filed on Oct. 5,2004; and 60/624,793, filed on Nov. 2, 2004. U.S. patent applicationSer. No. 11/266,993, filed Nov. 4, 2005, now U.S. Pat. No. 7,756,583, isa continuation-in-part of U.S. patent application Ser. No. 10/408,665,filed on Apr. 8, 2003, now U.S. Pat. No. 7,162,303, which claims thebenefit of U.S. Provisional Patent Application No. 60/442,970, filed onJan. 29, 2003; 60/415,575, filed on Oct. 3, 2002; and 60/370,190, filedon Apr. 8, 2002. Further, U.S. patent application Ser. No. 11/266,993,filed Nov. 4, 2005, now U.S. Pat. No. 7,756,583, is also acontinuation-in-part of co-pending U.S. patent application Ser. No.11/189,563, filed on Jul. 25, 2005, now U.S. Pat. No. 8,145,316.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

TECHNICAL FIELD

The present invention relates to methods and apparatus forneuromodulation. More particularly, the present invention relates tomethods and apparatus for achieving neuromodulation via anintravascularly-delivered pulsed electric field.

BACKGROUND

Congestive Heart Failure (“CHF”) is a condition that occurs when theheart becomes damaged and reduces blood flow to the organs of the body.If blood flow decreases sufficiently, kidney function becomes impaired,which results in fluid retention, abnormal hormone secretions andincreased constriction of blood vessels. These results increase theworkload of the heart and further decrease the capacity of the heart topump blood through the kidneys and circulatory system.

It is believed that progressively decreasing perfusion of the kidneys isa principal non-cardiac cause perpetuating the downward spiral of CHF.Moreover, the fluid overload and associated clinical symptoms resultingfrom these physiologic changes result in additional hospital admissions,poor quality of life and additional costs to the health care system.

In addition to their role in the progression of CHF, the kidneys play asignificant role in the progression of Chronic Renal Failure (“CRF”),End-Stage Renal Disease (“ESRD”), hypertension (pathologically highblood pressure) and other cardio-renal diseases. The functions of thekidneys can be summarized under three broad categories: filtering bloodand excreting waste products generated by the body's metabolism;regulating salt, water, electrolyte and acid-base balance; and secretinghormones to maintain vital organ blood flow. Without properlyfunctioning kidneys, a patient will suffer water retention, reducedurine flow and an accumulation of waste toxins in the blood and body.These conditions result from reduced renal function or renal failure(kidney failure) and are believed to increase the workload of the heart.In a CHF patient, renal failure will cause the heart to furtherdeteriorate as fluids are retained and blood toxins accumulate due tothe poorly functioning kidneys.

It has been established in animal models that the heart failurecondition results in abnormally high sympathetic activation of thekidneys. An increase in renal sympathetic nerve activity leads tovasoconstriction of blood vessels supplying the kidneys, decreased renalblood flow, decreased removal of water and sodium from the body, andincreased renin secretion. Reduction of sympathetic renal nerveactivity, e.g., via denervation, may reverse these processes.

Applicants have previously described methods and apparatus for treatingrenal disorders by applying a pulsed electric field to neural fibersthat contribute to renal function. See, for example, co-pending U.S.patent application Ser. No. 11/129,765, filed on May 13, 2005, and Ser.No. 11/189,563, filed on Jul. 25, 2005, both of which are incorporatedherein by reference in their entireties. A pulsed electric field (PEF)may initiate renal neuromodulation, e.g., denervation, for example, viairreversible electroporation or via electrofusion. The PEF may bedelivered from apparatus positioned intravascularly, extravascularly,transvascularly or a combination thereof. As used herein, electrofusioncomprises fusion of neighboring cells induced by exposure to an electricfield. Contact between target neighboring cells for the purposes ofelectrofusion may be achieved in a variety of ways, including, forexample, via dielectrophoresis. In tissue, the target cells may alreadybe in contact, facilitating electrofusion.

As used herein, electroporation and electropermeabilization are methodsof manipulating the cell membrane or intracellular apparatus. Forexample, the porosity of a cell membrane may be increased by inducing asufficient voltage across the cell membrane through, e.g., short,high-voltage pulses. The extent of porosity in the cell membrane (e.g.,size and number of pores) and the duration of effect (e.g., temporary orpermanent) are a function of multiple variables, such as field strength,pulse width, duty cycle, electric field orientation, cell type or sizeand other parameters.

Cell membrane pores will generally close spontaneously upon terminationof relatively lower strength electric fields or relatively shorter pulsewidths (herein defined as “reversible electroporation”). However, eachcell or cell type has a critical threshold above which pores do notclose such that pore formation is no longer reversible; this result isdefined as “irreversible electroporation,” “irreversible breakdown” or“irreversible damage.” At this point, the cell membrane ruptures and/orirreversible chemical imbalances caused by the high porosity occur. Suchhigh porosity can be the result of a single large hole and/or aplurality of smaller holes.

In some patients, when a PEF sufficient to initiate irreversibleelectroporation is applied to renal nerves and/or other neural fibersthat contribute to renal neural functions, applicants believe thatdenervation induced by the PEF would result in increased urine output,decreased plasma renin levels, decreased tissue (e.g., kidney) and/orurine catecholamines (e.g., norepinephrine), increased urinary sodiumexcretion, and/or controlled blood pressure. Such responses wouldprevent or treat CHF, hypertension, renal system diseases, and otherrenal or cardio-renal anomalies. PEF systems could be used to modulateefferent or afferent nerve signals, as well as combinations of efferentand afferent nerve signals.

A potential challenge of using intravascular PEF systems for treatingrenal disorders is to selectively electroporate target cells withoutaffecting other cells. For example, it may be desirable to irreversiblyelectroporate renal nerve cells that travel along or in proximity torenal vasculature, but it may not be desirable to damage the smoothmuscle cells of which the vasculature is composed. As a result, anoverly aggressive course of PEF therapy may persistently injure therenal vasculature, but an overly conservative course of PEF therapy maynot achieve the desired renal neuromodulation.

Applicants have previously described methods and apparatus formonitoring tissue impedance or conductivity to determine the effects ofpulsed electric field therapy, e.g., to determine an extent ofelectroporation and/or its degree of irreversibility. See, for example,Applicant's co-pending U.S. patent application Ser. No. 11/233,814,filed Sep. 23, 2005, incorporated by reference as set forth above.Pulsed electric field electroporation of tissue causes a decrease intissue impedance and an increase in tissue conductivity. If inducedelectroporation is reversible, tissue impedance and conductivity shouldapproximate baseline levels upon cessation of the pulsed electric field.However, if electroporation is irreversible, impedance and conductivitychanges should persist after terminating the pulsed electric field.Thus, monitoring the impedance or conductivity of target and/ornon-target tissue may be utilized to determine the onset ofelectroporation and to determine the type or extent of electroporation.Furthermore, monitoring data may be used in one or more manual orautomatic feedback loops to control the electroporation.

Even when monitoring techniques are utilized, the applied energy orvoltage from an intravascular PEF system necessary to establish anelectric field of sufficient magnitude to modulate target neural fibersthat contribute to renal function may be of a magnitude that causespersistent damage to non-target tissue, such as smooth muscle cells ofthe vessel wall. Thus, a desired treatment outcome, e.g., renaldenervation, may not be achievable with some intravascular PEF systemsin certain patients without concomitantly inducing persistent damage tothe non-target tissue. It therefore would be desirable to providemethods and apparatus for reducing the required magnitude of appliedvoltage delivered from an intravascular PEF system necessary to achievedesired neuromodulation in target tissue.

SUMMARY

The present invention provides methods and apparatus for achievingneuromodulation via an intravascularly-delivered pulsed electric field(“PEF”). In some embodiments, the intravascular PEF system comprises acatheter having a pair of bipolar electrodes for delivering the PEF,with a first electrode positioned on a first side of animpedance-altering element and a second electrode positioned on anopposing side of the impedance-altering element. A length of theelectrodes as well as a separation distance between the first and secondelectrodes may be specified such that, with the impedance-alteringelement deployed in a manner that locally increases impedance within apatient's vessel, a magnitude of applied voltage delivered across thebipolar electrodes necessary to achieve desired neuromodulation isreduced relative to an intravascular PEF system having similarly spacedelectrodes but no (or an undeployed) impedance-altering element. Forexample, the impedance-altering element can be deployed to contact thevessel wall at a treatment site within the patient's vasculature tolocally increase the impedance within a vessel. In a preferredembodiment, the impedance-altering element comprises an inflatableballoon configured to locally increase impedance within a patient'svasculature. The methods and apparatus of the present invention may beused to modulate a neural fiber that contributes to renal function.

Pulsed electric field parameters may be altered and combined in anycombination, as desired. Such parameters can include, but are notlimited to, voltage, field strength, pulse width, pulse duration, theshape of the pulse, the number of pulses and/or the interval betweenpulses (e.g., duty cycle), etc. Suitable field strengths include, forexample, strengths of up to about 10,000V/cm. Suitable pulse widthsinclude, for example, widths of up to about 1 second. Suitable shapes ofthe pulse waveform include, for example, AC waveforms, sinusoidal waves,cosine waves, combinations of sine and cosine waves, DC waveforms,DC-shifted AC waveforms, RF waveforms, square waves, trapezoidal waves,exponentially-decaying waves, combinations thereof, etc. Suitablenumbers of pulses include, for example, at least one pulse. Suitablepulse intervals include, for example, intervals less than about 10seconds. These parameters are provided for the sake of illustration andshould in no way be considered limiting.

BRIEF DESCRIPTION OF THE DRAWINGS

Several embodiments of the present invention will be apparent uponconsideration of the following detailed description, taken inconjunction with the accompanying drawings, in which like referencecharacters refer to like parts throughout, and in which:

FIG. 1 is a schematic view illustrating human renal anatomy.

FIG. 2 is a schematic detail view showing the location of the renalnerves relative to the renal artery.

FIGS. 3A and 3B are schematic side- and end-views, respectively,illustrating orienting of an electric field for selectively affectingrenal nerves.

FIG. 4 is a schematic view illustrating an exemplary intravascularmethod and apparatus for renal neuromodulation.

FIG. 5 is a schematic view illustrating an intravascular method andapparatus of the present invention.

FIG. 6 is a schematic view illustrating an alternative intravascularmethod and apparatus of the present invention.

FIGS. 7A-7D are schematic cross-sectional views illustrating FiniteElement Analysis modeling of spatial distributions of field strength forvarious intravascular PEF systems upon application of a constantmagnitude applied voltage across bipolar electrodes of the PEF systemswhile the electrodes are positioned within a patient's renal artery.

FIG. 8 is a graph illustrating modeling estimates of induced fieldstrength along the renal artery/fat interface with the PEF systems ofFIG. 7.

DETAILED DESCRIPTION A. Overview

The present invention relates to methods and apparatus forneuromodulation, e.g., denervation. More particularly, the presentinvention relates to methods and apparatus for achieving neuromodulationvia an intravascularly-delivered pulsed electric field. In someembodiments, the intravascular PEF system comprises a catheter having apair of bipolar electrodes for delivering the PEF, with a firstelectrode positioned on a first side of an impedance-altering elementand a second electrode positioned on an opposing side of theimpedance-altering element. A length of the electrodes, as well as aseparation distance between the first and second electrodes, may bespecified such that a magnitude of applied voltage delivered across thebipolar electrodes necessary to achieve desired neuromodulation isreduced relative to an intravascular PEF system having similarly spacedelectrodes but no (or an undeployed) impedance-altering element.

The methods and apparatus of the present invention may be used tomodulate a neural fiber that contributes to renal function and mayexploit any suitable electrical signal or field parameters, e.g., anyelectric field that will achieve the desired neuromodulation (e.g.,electroporative effect). To better understand the structures of devicesof the present invention and the methods of using such devices for renalneuromodulation and monitoring, it is instructive to examine the renalanatomy in humans.

B. Selected Embodiments of Methods for Neuromodulation

With reference now to FIG. 1, the human renal anatomy includes kidneys Kthat are supplied with oxygenated blood by renal arteries RA, which areconnected to the heart by the abdominal aorta AA. Deoxygenated bloodflows from the kidneys to the heart via renal veins RV and the inferiorvena cava IVC. FIG. 2 illustrates a portion of the renal anatomy ingreater detail. More specifically, the renal anatomy also includes renalnerves RN extending longitudinally along the lengthwise dimension L ofrenal artery RA generally within the adventitia of the artery. The renalartery RA has smooth muscle cells SMC that surround the arterialcircumference and spiral around the angular axis 8 of the artery. Thesmooth muscle cells of the renal artery accordingly have a lengthwise orlonger dimension extending transverse (i.e., non-parallel) to thelengthwise dimension of the renal artery. The misalignment of thelengthwise dimensions of the renal nerves and the smooth muscle cells isdefined as “cellular misalignment.”

Referring to FIG. 3, the cellular misalignment of the renal nerves andthe smooth muscle cells may be exploited to selectively affect renalnerve cells with reduced effect on smooth muscle cells. Morespecifically, because larger cells require a lower electric fieldstrength to exceed the cell membrane irreversibility threshold voltageor energy for irreversible electroporation, several embodiments ofelectrodes of the present invention are configured to align at least aportion of an electric field generated by the electrodes with or nearthe longer dimensions of the cells to be affected. In specificembodiments, the device has electrodes configured to create anelectrical field aligned with or near the lengthwise dimension L of therenal artery RA to affect renal nerves RN. By aligning an electric fieldso that the field preferentially aligns with the lengthwise aspect ofthe cell rather than the diametric or radial aspect of the cell, lowerfield strengths may be used to affect target neural cells, e.g., tonecrose or fuse the target cells, to induce apoptosis, to alter geneexpression, to change cytokine upregulation, etc. This is expected toreduce total energy delivered to the system and to mitigate effects onnon-target cells in the electric field.

Similarly, the lengthwise or longer dimensions of tissues overlying orunderlying the target nerve are orthogonal or otherwise off-axis (e.g.,transverse) with respect to the longer dimensions of the nerve cells.Thus, in addition to aligning the PEF with the lengthwise or longerdimensions of the target cells, the PEF may propagate along the lateralor shorter dimensions of the non-target cells (i.e., such that the PEFpropagates at least partially out of alignment with non-target smoothmuscle cells SMC). Therefore, as seen in FIG. 3, applying a PEF withpropagation lines Li generally aligned with the longitudinal dimension Lof the renal artery RA is expected to preferentially causeelectroporation, electrofusion, denervation or other neuromodulation incells of the target renal nerves RN without unduly affecting thenon-target arterial smooth muscle cells SMC. The pulsed electric fieldmay propagate in a single plane along the longitudinal axis of the renalartery, or may propagate in the longitudinal direction along any angularsegment 8 through a range of 0°-360°.

A PEF system placed within and/or at least partially across the wall ofthe renal artery may propagate an electric field having a longitudinalportion that is aligned to run with the longitudinal dimension of theartery in the region of the renal nerves RN and the smooth muscle cellSMC of the vessel wall so that the wall of the artery remains at leastsubstantially intact while the outer nerve cells are destroyed, fused orotherwise affected. Monitoring elements may be utilized to assess anextent of, e.g., electroporation, induced in renal nerves and/or insmooth muscle cells, as well as to adjust PEF parameters to achieve adesired effect.

C. Exemplary Embodiments of Systems and Additional Methods forNeuromodulation

With reference to FIG. 4, an embodiment of an intravascular PEF systemand method is described. The system is configured for temporaryintravascular placement. Furthermore, the system is configured todeliver a pulsed electric field to neural fibers for neuromodulation,e.g., to deliver the pulsed electric field to neural fibers thatcontribute to renal function in order to achieve renal neuromodulation.Intravascular pulsed electric field apparatus 100 comprises catheter 102having a pair of bipolar electrodes 104 positioned along the shaft ofthe catheter. The electrodes are electrically connected to pulsedelectric field generator 50 located external to the patient. Thegenerator may be utilized with any embodiment of the present inventionfor delivery of a PEF with desired field parameters. It should beunderstood that PEF-delivery electrodes of embodiments describedhereinafter may be electrically connected to the generator, even thoughthe generator is not explicitly shown or described with each embodiment.The electrodes may, for example, be fabricated from wound coils of wire.When utilizing relatively long electrodes, wound coils allow thecatheter to maintain a desired degree of flexibility.

In use, catheter 102 may, for example, be delivered to renal artery RAas shown, or may be delivered to a renal vein or to any other vessel inproximity to neural tissue contributing to renal function, for example,through a guide catheter. Once positioned within the patient'svasculature, a pulsed electric field may be generated by the PEFgenerator 50, transferred through catheter 102 to electrodes 104, anddelivered via the electrodes 104 across the wall of the vasculature. ThePEF therapy modulates the activity along neural fibers, for example,along neural fibers that contribute to renal function, e.g., denervatesthe neural fibers. This may be achieved, for example, via irreversibleelectroporation, electrofusion, necrosis and/or inducement of apoptosisin the nerve cells, alteration of gene expression, changes in cytokineupregulation, etc. In many applications, including that shown in FIG. 4,the electrodes are arranged so that the pulsed electric field is alignedwith the longitudinal dimension of the renal artery to facilitatemodulation of renal nerves with limited effect on non-target smoothmuscle cells or other cells.

It is expected that PEF therapy will alleviate clinical symptoms of CHF,hypertension, renal disease and/or other cardio-renal diseases for aperiod of months, potentially up to six months or more. This time periodmight be sufficient to allow the body to heal; for example, this periodmight reduce the risk of CHF onset after an acute myocardial infarction,thereby alleviating a need for subsequent re-treatment. Alternatively,as symptoms reoccur, or at regularly scheduled intervals, the patientmight return to the physician for a repeat therapy.

In order to denervate target neural fibers, apparatus 100 must generatean electric field of sufficient strength or magnitude across the fibersto induce such denervation. Depending upon the arrangement andpositioning of electrodes 104 and catheter 102, as well as thephysiology of the patient, the applied voltage necessary to achieve afield strength of sufficient magnitude at the neural fibers might alsobe of sufficient magnitude to induce undesirable persistent injury innon-target tissue, such as smooth muscle cells and/or the vessel wall.It therefore would be desirable to provide apparatus and methods thatreduce the necessary applied voltage for intravascular renal denervationvia PEF therapy, as compared to the applied voltage required whenutilizing apparatus 100.

Referring now to FIG. 5, an embodiment of an intravascular PEF system ofthe present invention is described. This embodiment includes anapparatus 200 comprising a catheter 202 having impedance-alteringelement 204, such as an inflatable balloon, an expandable cage (e.g., apolymer-coated expandable wire cage) or some other expandable element.Several embodiments of the impedance altering element 204 are configuredto center electrodes 206 within a vessel. In a preferred embodiment,impedance-altering element 204 is configured to locally increaseimpedance within a patient's vasculature. In a further preferredembodiment, impedance-altering element 204 comprises an inflatableballoon, as shown in FIG. 5.

PEF-delivery electrodes 206 a and 206 b are positioned along the shaftof catheter 202 with known separation distance D; and optionalradiopaque markers 208 are positioned along the shaft of the catheter inthe region of impedance-altering element 204. The radiopaque markers 208can be spaced apart from each other along a balloon-typeimpedance-altering element by known separation distance d. Theelectrodes 206 a-b, for example, can be arranged such that the electrode206 a is near a proximal end of element 204 and the electrode 206 b isnear a distal end of the element 204. Electrodes 206 are electricallycoupled to pulse generator 50 (see FIG. 4), which is positioned externalto the patient, for delivery of PEF therapy. Radiopaque markersadditionally or alternatively may be located along the shaft of catheter202 outside of element 204, as illustrated by radiopaque markets 208′.As yet another alternative or addition, electrodes 206 may be fabricatedfrom a radiopaque material, such as platinum, and utilized as radiopaquemarkers.

Apparatus 200 may further comprise optional monitoring electrodes 210,illustratively also with known separation distance d. Applicants havepreviously described the use of such monitoring electrodes to monitortissue impedance or conductivity for determining the effects of pulsedelectric field therapy, e.g., for determining an extent ofelectroporation and/or its degree of irreversibility. See, for example,Applicant's co-pending U.S. patent application Ser. No. 11/233,814,filed Sep. 23, 2005, which is incorporated herein by reference as setforth above. Pulsed electric field electroporation of tissue causes adecrease in tissue impedance and an increase in tissue conductivity. Ifinduced electroporation is reversible, tissue impedance and conductivityshould approximate baseline levels upon cessation of the pulsed electricfield. However, if electroporation is irreversible, impedance andconductivity changes should persist after termination of the pulsedelectric field. Thus, monitoring of the impedance or conductivity oftarget and/or non-target tissue via electrodes 210 may be utilized todetermine the onset of electroporation and/or to determine the type orextent of electroporation. Furthermore, monitoring data may be used inone or more manual or automatic feedback loops to control theelectroporation.

Regardless of whether the effects of PEF therapy are monitored, themagnitude of voltage applied across electrodes 206 in order to establishan electric field of sufficient magnitude to modulate target neuralfibers that contribute to renal function also might be of a magnitudethat causes persistent damage to non-target tissue, such as smoothmuscle cells of the vessel wall. Thus, a desired treatment outcome,e.g., renal denervation, might not be achievable in certain patientswithout concomitantly inducing persistent damage to the non-targettissue.

In accordance with the principles of the present invention,impedance-altering element 204 may reduce the magnitude of voltageapplied across electrodes 206 that is required to modulate the targetneural fibers. In some patients, this reduction in magnitude might lowerthe applied voltage below a threshold level that would cause theundesirable persistent damage to the non-target tissue. Element 204 mayachieve this reduction in applied voltage magnitude, for example, bylocally increasing impedance within the renal vasculature. Element 204additionally or alternatively may facilitate use of a common appliedvoltage across a wider range of vessel sizes.

In embodiments where the impedance-altering element 204 comprises aninflatable balloon configured to temporarily occlude blood flow duringdelivery of PEF therapy across electrodes 206, the occluding balloon mayserve as an electrical insulator that locally increases electricalimpedance during PEF delivery. This impedance increase may direct anelectric field delivered across electrodes 206, e.g., may direct theelectric field into or across the vessel wall for modulation of targetneural fibers. The impedance-altering element 204 electrically insulatesa portion of the vessel in a manner that may reduce the magnitude ofapplied voltage or other parameters of the pulsed electric fieldnecessary to achieve a desired field strength at the target fiberscompared to apparatus 100 of FIG. 4 that does not comprise animpedance-altering element. The desired field strength, for example, mayhave a magnitude sufficient to denervate the target fibers viaelectroporation. As discussed, this reduction may moderate persistentdamage to the non-target tissue. Furthermore, by substantially centeringelectrodes 206 within the vessel before delivery of PEF therapy, element204 may further reduce a potential of persistent damage to thenon-target tissue of the vessel wall, etc., and/or may facilitatedelivery of a more concentrically uniform electric field to the targetneural fibers surrounding the renal artery. In addition, or as analternative, to the use of balloon element 204 to achieve a desiredinsulation or impedance increase within a patient's vasculature betweenelectrodes 206 during delivery of PEF therapy, the impedance change maybe achieved via an insulative covering, e.g., via a polymeric tube orsleeve with closed ends, positioned about a mechanical activationmember. The mechanical activation member may be configured to expand theinsulative covering into, e.g., circumferential sealing contact with thevessel wall. The mechanical activation member may, for example, comprisean expandable cage. Additional methods and apparatus in accordance withthe present invention for achieving the desired impedance change will beapparent to those of skill in the art.

With reference now to FIG. 6, an alternative embodiment of apparatus 200is described. In FIG. 5, impedance-altering element 204 illustrativelycomprises a semi-compliant balloon that contacts renal artery RA over alength of the artery. In FIG. 6, element 204′ illustratively comprises asubstantially non-compliant balloon that contacts the renal artery morefocally, e.g., substantially tangentially. Balloon element 204′ of FIG.6 may have a shorter length than balloon element 204 of FIG. 5, therebyfacilitating a shorter separation distance D between PEF-deliveryelectrodes 206.

Finite Element Analysis (“FEA”) modeling of induced electric fieldstrengths from various embodiments of intravascular PEF systems has beenconducted to guide the design of preferred intravascular PEF systemembodiments that reduce the required applied voltage needed to achieve adesired field strength at target tissue. Modeled variables of theintravascular PEF system designs included use (or lack thereof) of anelement configured to locally increase impedance within a patient'svasculature (e.g., a balloon element), the physical design of theimpedance-altering element, electrode size (not shown) and electrodespacing (not shown). Varying vessel diameter also was modeled.

With reference to FIGS. 7 and 8, the FEA modeling results for fourexemplary intravascular PEF systems are provided. Each of the foursystems was modeled with a constant applied voltage across theelectrodes (e.g., 360V), a constant electrode size (e.g., 6 mm), and aconstant electrode separation distance (e.g., 10 mm) within a vessel ofconstant diameter (e.g., 3.5 mm). These models facilitate study of theeffect of the design of the impedance-altering element on induced fieldstrength at target tissue. In FIGS. 7 and 8, the PEF electrodesillustratively are centered with the vessel. The impedance-alteringelement preferably facilitates centering of the electrodes within thevessel.

As seen in FIG. 7A, the first PEF system embodiment comprises avariation of apparatus 100 of FIG. 4 that does not comprise animpedance-altering element or that comprises an undeployedimpedance-altering element, such as a deflated balloon element. As seenin FIG. 7B, the second embodiment comprises a variation of apparatus 200of FIG. 5 comprising a 5 mm-long balloon element configured to alterimpedance within a patient's vasculature, illustratively asemi-compliant balloon. In FIG. 7C, the third embodiment comprises avariation of apparatus 200 of FIG. 6 wherein balloon element 204′ is 4mm long, illustratively non-compliant, and makes only tangential contactwith the wall of the renal artery RA. In FIG. 7D, the fourth embodimentcomprises another variation of apparatus 200 wherein the balloon element204″ comprises a disc that occludes the renal artery RA over a veryshort length and makes substantially tangential wall contact.

The four embodiments each comprise a pair of bipolar PEF-deliveryelectrodes (electrodes 104 in FIG. 7A and electrodes 206 in FIGS. 7B-7D)with a constant separation distance D between each of the electrodese.g., 10 mm), and a constant electrode length L (e.g., 6 mm). Similarmodeling was conducted with a separation distance of 20 mm between theelectrodes (not shown), and it was determined that a separation distanceof less than about 20 mm is desirable in order to significantly alterthe requisite magnitude of applied voltage needed with an inflatedballoon to achieve a desired field strength magnitude along targetneural tissue. Use of a balloon element when the electrode spacing wasabout 20 mm or greater showed little difference in required appliedvoltage between when a balloon was, and was not, used.

Electrodes 206 illustratively comprise 6 mm electrodes. Modeling alsowas conducted with 3 mm electrodes (not shown), and it was determinedthat the required applied voltage for a given field strength at targettissue generally increases as electrode length decreases. Thus, itgenerally is desirable to have longer electrodes, for example,electrodes preferably longer than about 1 mm, even more preferablylonger than about 2 mm.

FIG. 8 provides a graph illustrating modeling estimates of induced fieldstrength in the vicinity of target neural fibers along the renal arteryRA/fat F interface I when 360V are applied across modeled bipolarelectrodes of the modeled PEF system embodiments of FIG. 7. FIGS. 7 and8 illustrate that, for the modeled PEF system designs, use of animpedance-altering element such as a balloon directs the electricalfield across the wall of the renal artery. Furthermore, the peak fieldstrength induced in the vicinity of the target neural fibers, i.e., atinterface I, is increased. Thus, a lower applied voltage may be requiredto obtain a desired peak electric field strength at interface I when animpedance-altering element is utilized, as compared to when noimpedance-altering element is provided or when the impedance-alteringelement is not deployed (e.g., when a balloon element is not inflated).

The modeled systems of FIGS. 7 and 8 illustrate that the contact lengthbetween the impedance-altering element and the vessel wall does notsubstantially alter the peak electric field strength at the interface,so long as some wall contact exists. Furthermore, shorter contactlengths, e.g., contact lengths achieved with balloon elements havinglengths of less than about 5 mm, do not substantially alter the peakelectric field strength. Additional FEA models (not shown) illustratethat, for the 10 mm spacing of the bipolar electrodes and a givenapplied voltage, use of an impedance-altering element substantiallyreduces changes in peak electric field strength associated with changesin vessel diameter, as compared to PEF systems without, or withundeployed, impedance-altering elements, suggesting that a substantiallyconstant applied voltage may be used to achieve a desired electric fieldstrength over a variety of vessel sizes when an impedance-alteringelement is used. This is in contrast to PEF system embodiments lackingimpedance-altering elements; such embodiments might require increasingapplied voltages with increasing vessel diameter in order to achieve agiven desired peak electric field strength. The range of vessel sizesover which an impedance-altering PEF system may apply a substantiallyconstant voltage to achieve a substantially similar peak field strengthat the interface may, for example, vary between about 3 mm and 9 mm.

Although preferred illustrative variations of the present invention aredescribed above, it will be apparent to those skilled in the art thatvarious changes and modifications may be made thereto without departingfrom the invention. For example, although the variations primarily havebeen described for use in combination with pulsed electric fields, itshould be understood that any other electric field may be delivered asdesired. It is intended in the appended claims to cover all such changesand modifications that fall within the true spirit and scope of theinvention.

We claim:
 1. A method for treating a hypertensive human patient, themethod comprising: positioning a catheter within a renal artery of thepatient and proximate to renal nerves innervating a kidney of thepatient; transforming an impedance-altering element at a distal portionof the catheter from a low-profile delivery configuration to an expandedtreatment configuration within the renal artery; and inhibiting neuralsignaling along the renal nerves via thermal energy from a pair ofbipolar electrodes carried by the catheter, wherein the pair of bipolarelectrodes are positioned on a shaft of the catheter on opposite ends ofand external to the impedance-altering element, wherein theimpedance-altering element is configured to locally increase impedancebetween the pair of bipolar electrodes during intravascular delivery ofthe thermal energy, and wherein inhibiting neural signaling along therenal nerves results in a therapeutically beneficial reduction in bloodpressure of the patient.
 2. The method of claim 1 wherein inhibitingneural signaling along the renal nerves via thermal energy comprisesablating the renal nerves via electrical energy delivered by the pair ofbipolar electrodes.
 3. The method of claim 1 wherein inhibiting neuralsignaling along the renal nerves via thermal energy comprises partiallyablating the renal nerves via electrical energy delivered by the pair ofbipolar electrodes.
 4. The method of claim 1 wherein inhibiting neuralsignaling along the renal nerves via thermal energy comprises inhibitingneural signaling along the renal nerves via radio frequency (RF) energydelivered by the pair of bipolar electrodes.
 5. The method of claim 1wherein inhibiting neural signaling along the renal nerves via thermalenergy comprises inhibiting neural signaling along the renal nerves viapulsed electrical energy delivered by the pair of bipolar electrodes. 6.The method of claim 1 wherein inhibiting neural signaling along therenal nerves via thermal energy comprises at least partially denervatingthe kidney of the patient.
 7. The method of claim 1 wherein theimpedance-altering element comprises a balloon, and wherein, in theexpanded treatment configuration, the balloon is sized and shaped totemporarily occlude blood flow within the renal artery.
 8. The method ofclaim 1 wherein the impedance-altering element comprises asemi-compliant balloon.
 9. The method of claim 1 wherein theimpedance-altering element comprises a non-compliant balloon.
 10. Themethod of claim 1 wherein the impedance-altering element comprises anexpandable cage, and wherein, in the expanded treatment configurationwithin the renal artery, the expandable cage does not occlude blood flowwithin the renal artery.
 11. The method of claim 1 wherein theimpedance-altering element comprises a balloon, and wherein, in theexpanded treatment configuration, the balloon has a length of 5 mm. 12.The method of claim 1 wherein the impedance-altering element comprises aballoon, and wherein, in the expanded treatment configuration, theballoon has a length of 4 mm.
 13. The method of claim 1 wherein theimpedance-altering element comprises a disc-shaped balloon, and wherein,in the expanded treatment configuration, the balloon is sized and shapedto make substantially tangential wall contact.
 14. The method of claim 1wherein locally increasing impedance further comprises directing thethermal field across a wall of the renal artery between the pair ofbipolar electrodes.
 15. The method of claim 1 wherein positioning acatheter within a renal artery of the patient comprises intravascularlydelivering the catheter to the renal artery over a guidewire.
 16. Themethod of claim 1 wherein positioning a catheter within a renal arteryof the patient comprises intravascularly delivering the catheter to therenal artery within a guide catheter.
 17. The method of claim 1, furthercomprising: transforming the impedance-altering element from theexpanded treatment configuration to the low-profile deliveryconfiguration; and removing the catheter from the patient afterdelivering thermal energy via the pair of bipolar electrodes to concludethe procedure.
 18. The method of claim 1, further comprising monitoringa parameter of target tissue and/or non-target tissue within the patientbefore and during delivery of the thermal energy.
 19. The method ofclaim 18 wherein monitoring a parameter comprises monitoring atemperature of target tissue, and wherein the method further comprisesmaintaining the target tissue at a desired temperature during deliveryof the thermal energy.
 20. The method of claim 18, further comprisingaltering delivery of the thermal energy in response to the monitoredparameter.